The goal of the proposed experiments is a continued characterization of the cellular mechanisms underlying glutamate neurotoxicity, a process which may participate in the neuronal degeneration associated with certain acute or chronic neurological diseases, including Alzheimer's disease. Even is glutamate neurotoxicity is not involved in the pathogenesis of any chronic neurodegenerative diseases, it is proposed that elucidation of its underlying mechanisms could yield valuable insights into some common principles of neuronal cell injury. To achieve cellular and molecular resolution, investigations will take place in an established dissociated murine cortical cell culture model system. Using pharmacological, physiological, and neurochemical approaches, including neurotoxicity assays, histochemical stains, whole cell recording, HPLC, 45Ca2+ accumulation, and fura-2 videomicroscopy, answers to these four questions will be specifically sought: 1) What is the role of the "metabotropic" glutamate receptor in glutamate neurotoxicity? 2) What is the role of calcium in glutamate neurotoxicity? 3) What is the role of lipid peroxidation in mediating glutamate neurotoxicity? and 4) Why are cortical neurons containing high concentrations of NADPH-diaphorase resistant to NMDA receptor- mediated injury? The proposed experiments will provide new information regarding the nature of glutamate neurotoxicity and could lead to the development of therapeutic approaches designed to reduce pathological neuronal cell death in Alzheimer's disease or related disorders.